What's in a Number?

Numbers mean a lot in the practice of medicine. It is numbers that are used to set treatment goals. These numbers serve as "surrogates" for the outcomes that we really care about, like heart attacks and strokes. Think, for example, of the low-density lipoprotein (LDL) cholesterol goal of less than 100 mg/dl, or the A1C goal of less than 7 percent.

The use of surrogate numbers has been critical to unraveling complex disease mechanisms, developing clinical practice guidelines, and discovering new medications. These surrogates are used by the U.S. Food and Drug Administration in the evaluation of medications, and a recent study in the Journal of the American Medical Association found that four out of five diabetes trials are using surrogate measures as primary outcomes of their studies. So it is worth pausing for a moment to consider numbers in the context of a couple of recent clinical trials that were widely reported in the press.

The ENHANCE trial was designed to test a more aggressive LDL cholesterol goal, and the ADVANCE and ACCORD trials were designed to test more aggressive A1C goals. While scientific debate regarding the implications of these trials continues, they have reminded us of an important principle in clinical research. Namely, it is easier to reduce risk when risk is high.

That means that the risk from high cholesterol, high blood pressure, or high blood glucose is greater when the level of those measures is higher. Older studies proved beyond doubt the benefit of reducing high blood pressure, high cholesterol, and high blood glucose. Those definitive studies are the basis of the current treatment recommendations from the American Diabetes Association and other authorities. Unlike many of those older trials, the newer ones, including ENHANCE, ADVANCE, and ACCORD, were designed to test a good level of control compared to an even better level of control. In a sense, there is no real placebo group in these studies: Everyone got treatment.

That difference is critical because while these newer trials have produced results that are less clear, they in no way invalidate the use of LDL cholesterol or A1C as a treatment surrogate for people with diabetes. Rather, what they teach us is that while there is a lot of benefit to be gained by reducing high blood glucose or high blood cholesterol, there is not as much benefit to be gained by reducing an already pretty low value to an even lower value. The debate here is in fact not if we should lower blood glucose and blood cholesterol but rather how low to go. While that point has been a little lost in the sometimes sensationalistic coverage of these trials by the mainstream press, it is a point that clinicians—and people with diabetes—cannot afford to forget.